DISCUSSION: Allosteric effectors reduce the oxygen affinity of hemoglobin allowing for greater tissue oxygenation. The goal of the research program is to develop a new class of pharmaceutical agents that would be the first of their kind, which enhance tissue oxygenation. Many disease states would benefit significantly from an increase in cellular oxygen delivery. The overall intent of the phase I proposal will involve the design, synthesis, structural determination, and assessment of the biological efficacy of the potential allosteric modifiers of human HbA, for potential clinical uses. The specific goals will include: a) the rational design of novel allosteric modifiers of human hemoglobin, employing a structure-based approach and molecular modeling based on the X-ray crystallographic binding data of two lead molecules, RSR4 and RSR13, b) determination of the X-ray crystallographic binding of specific drug-HbA atom-atom interactions contributing to the allosteric activity of these compounds and c) the evaluation of the in vitro and in vivo pharmacologic and pharmacokinetic activity of these agents by measuring alterations in the whole blood oxygen affinity.